Alcoholic liver disease (ALD) afflicts an estimated 2 million patients in the US with an astounding 65% mortality rate over a 4 year period. We hypothesize that acute or chronic alcohol abuse alters homeostatic balance that exists between intracellular mediators and suppressors of proinflammatory signaling. This signaling culminates in genetic reprogramming of liver cells manifested by expression of proinflammatory and proapoptotic mediators. We will study how ethanol alters the opposing roles of two key intracellular mediators, signal transducer and activator of transcription (STAT) 1 and 3 in T cell-mediated hepatitis model. The alcohol-induced imbalance between potentially harmful (proapoptotic) signaling mediated by STAT1 and beneficial (anti-apoptotic) signaling mediated by STATS will be studied using our new strategy termed intracellular protein therapy to target proinflammatory and proapoptotic signaling resulting from excessive STAT1 activation. We will expand our successful design and in vivo delivery of physiologic suppressors of cytokine signaling to the cytoplasmic protein known to ablate proinflammatory signaling in macrophages (Kupffer cells) which play a significant role in alcohol-associated inflammatory liver injury. Moreover, we have developed a cell-penetrating nuclear import inhibitory peptide as a prototype of a new class of anti- inflammatory and anti-apoptotic agents which suppresses production of proinflammatory cytokines/chemokines, prevents massive liver apoptosis/necrosis mediated by T cells or macrophages, and reduces mortality rates in animal models. Since this cell-penetrating peptide inhibitor targets intracellular adaptors responsible for nuclear import of stress responsive transcription factors, we will analyze the role of nuclear import adaptors in alcohol-induced injury of liver cells. Cumulatively, we anticipate that the new knowledge gained from these studies will, advance our concept of intracellular protein therapy to extinguish alcohol-exacerbated liver inflammation and apoptosis, and contribute to the development of new therapies for the rapidly failing liver among an estimated 2 million ALD patients in the US. Based on the overall workscope, this grant application is submitted in response to PA-05-074 """"""""Mechanisms of Alcohol-Induced Tissue Injury"""""""".

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015752-04
Application #
7764626
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Gao, Peter
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$341,921
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hawiger, J; Veach, R A; Zienkiewicz, J (2015) New paradigms in sepsis: from prevention to protection of failing microcirculation. J Thromb Haemost 13:1743-56
Qiao, Huan; Liu, Yan; Veach, Ruth A et al. (2014) The adaptor CRADD/RAIDD controls activation of endothelial cells by proinflammatory stimuli. J Biol Chem 289:21973-83
Liu, Yan; Major, Amy S; Zienkiewicz, Jozef et al. (2013) Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver. J Am Heart Assoc 2:e000093
Zienkiewicz, Jozef; Armitage, Amy; Hawiger, Jacek (2013) Targeting nuclear import shuttles, importins/karyopherins alpha by a peptide mimicking the NF?B1/p50 nuclear localization sequence. J Am Heart Assoc 2:e000386
Sethman, Chad R; Hawiger, Jacek (2013) The innate immunity adaptor SARM translocates to the nucleus to stabilize lamins and prevent DNA fragmentation in response to pro-apoptotic signaling. PLoS One 8:e70994
Lin, Qing; Liu, Yan; Moore, Daniel J et al. (2012) Cutting edge: the ""death"" adaptor CRADD/RAIDD targets BCL10 and suppresses agonist-induced cytokine expression in T lymphocytes. J Immunol 188:2493-7
Fletcher, Tynetta C; DiGiandomenico, Antonio; Hawiger, Jacek (2010) Extended anti-inflammatory action of a degradation-resistant mutant of cell-penetrating suppressor of cytokine signaling 3. J Biol Chem 285:18727-36